We have shown that pharmacological inhibition of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), blocks nicotine self-administration and prevents nicotine-induced reinstatement in squirrel monkeys, a model of human nicotine addiction and relapse to nicotine use. Based on these results, which point to FAAH as a promising molecular target for tobacco dependence, we propose to undertake a drug discovery program aimed at the optimization and preclinical development of FAAH inhibitors for smoking cessation. Our proposal has two primary goals: Specific Aim 1: Optimization of FAAH inhibitors and identification of a preclinical candidate for smoking cessation. We will conduct a lead optimization campaign starting from the compound URB694, a potent FAAH inhibitor previously identified in our laboratory. Compounds will be synthesized and tested in vitro and in vivo, and information collected will be used to design new molecules until a preclinical candidate with suitable efficacy and safety profile is selected. Specific Aim 2: Preclinical development of FAAH inhibitors for smoking cessation. We will (a) advance through preclinical development the candidate identified in Aim 1; (b) prepare and submit an Investigational New Drug (IND) application for the candidate with smoking cessation as therapeutic target; (c) seek private and/or public sponsors to support safety and proof-of-concept studies in humans after IND approval. To achieve these goals, we have assembled a multi-disciplinary consortium that unites scientific excellence with experience in industrial drug discovery and preclinical development. The team includes scientist and entrepreneur Daniele Piomelli (UCI), a leader in the field of FAAH inhibition; behavioral pharmacologist Steven Goldberg (NIDA-IRP), a pioneer in nicotine research; senior chemist Tiziano Bandiera (IIT); senior pharmacologist Angelo Reggiani (IIT); and preclinical development expert Edward Monaghan. Thus, our team combines the experience and skills required to translate an important research finding into a potential new treatment for tobacco dependence.